The candidate is formally trained in medicine and electrical engineering with prior research experience that has applied principles of electromechanics to investigations of cartilage and osteoarthritis. This proposal will allow the candidate a mentored period to learn to conduct molecular cell biology research in cardiovascular disease and develop an independent research career focused on quantitative understanding of cellular redox signaling networks in vascular disease. This proposal will focus on understanding the role of thioredoxin interacting protein (Txnip), which binds and inhibits thioredoxin, in diabetic vascular disease. Txnip has been shown to inhibit vascular smooth muscle cell proliferation and promote apoptosis by manipulation of the cellular redox state. A surprising new finding is that Txnip is strongly induced by high glucose concentrations. Since there is good evidence that diabetic vascular disease is caused in part by dysregulation of the cellular redox state, this has led to the central hypothesis that the regulation of Txnip by glucose impairs vascular thioredoxin activity, leading to increased oxidative stress and promoting vascular injury in diabetes. The aims of this proposal are to test the hypothesis that 1) the induction of Txnip by glucose promotes a pro- apoptotic state in vascular cells through blockade of thioredoxin's antioxidant function, using molecular cell biology techniques as well as live-cell imaging modalities for quantitative modeling of the Txnip-thioredoxin interaction;and 2) Txnip regulates redox state in diabetic arteries in mice, using tissue-specific targeted gene deletion. These experiments are critical for understanding Txnip and thioredoxin's roles in vascular disease and may reveal a new fundamental pathway for diabetic vascular injury, which is a major contributor to morbidity and mortality in diabetic patients. People with diabetes have an increased risk of heart attack and other diseases due to problems with their blood vessels. The reasons are not clear but one reason is increased stress on the cells due to oxidation. This proposal will study a system the cells normally use to control oxidative stress and test whether this system could cause the death of cells in diabetes due to the high glucose levels in the blood. (End of Abstract)